Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.10 (IKK)
 4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies on rodents and humans demonstrate an inherited predisposition to hepatocellular carcinoma (HCC). Analysis of the molecular alterations involved in the acquisition of a phenotype resistant or susceptible to hepatocarcinogenesis showed a deregulation of G1 and S phases in HCC of genetically susceptible F344 rats and a G1-S block in lesions of resistant Brown norway (BN) rats. Unrestrained extracellular signal-regulated kinase (ERK) activity linked to proteasomal degradation of dual-specificity phosphatase 1 (DUSP1), a specific ERK inhibitor, by the CKS1-SKP2 ubiquitin ligase complex occurs in more aggressive HCC of F344 rats and humans. This mechanism is less active in HCC of BN rats and human HCC with better prognosis. Upregulation of iNos cross-talk with IKK/NF-kappaB and RAS/ERK pathways occurs in rodent liver lesions at higher levels in the most aggressive models represented by HCC of F344 rats and c-Myc-TGF-alpha transgenic mice. iNOS, IKK/NF-kappaB, and RAS/ERK upregulation is highest in human HCC with a poorer prognosis and positively correlates with tumor proliferation, genomic instability and microvascularization, and negatively with apoptosis. Thus, cell cycle regulation and the activity of signal transduction pathways seem to be modulated by HCC modifier genes, and differences in their efficiency influence the susceptibility to hepatocarcinogenesis and probably the prognosis of human HCC.
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PMID:Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis. 1903 60

The BRAFV600E mutation is common in human melanoma. This mutation enhances IkappaB kinase (IKK)/nuclear factor-kappaB (NF-kappaB) and extracellular signal-regulated kinase/activator protein signaling cascades. In this study, we evaluated the efficacy of targeting either B-Raf or IKKbeta in combination with the DNA alkylating agent temozolomide for treatment of advanced metastatic melanoma. Xenografts of Hs294T human metastatic melanoma cells exhibiting the BRAFV600E mutation were treated with inhibitors of IKKbeta (BMS-345541), B-Raf (BAY 54-9085), and/or temozolomide. Drug response was mechanistically analyzed in vitro and in vivo. In this study, we determined that the antitumor activity of all three drugs depends on inhibition of NF-kappaB. BMS-345541 inhibits IKKbeta-mediated phosphorylation of IkappaBalpha and thus blocks the nuclear localization of NF-kappaB, whereas BAY 54-9085 inhibits activation of NF-kappaB through a mechanism that does not involve stabilization of IkappaBalpha. Moreover, BMS-345541, but not BAY 54-9085, activates the death pathways of p53 and c-Jun-NH2-kinase, contributing to the killing of melanoma cells. Temozolomide inhibits both NF-kappaB and extracellular signal-regulated kinase activity, conferring effective in vivo antitumor activity. Thus, temozolomide, but not BAY 54-9085, has a synergistic in vivo antitumor effect with BMS-345541. We conclude that the efficacy of antimelanoma therapy depends on inhibition of expression of antiapoptotic genes transcriptionally regulated by NF-kappaB. In contrast, drug targeting of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway alone in melanoma cells is ineffective for melanoma therapy in cases where NF-kappaB is not also targeted.
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PMID:Molecular determinants of melanoma malignancy: selecting targets for improved efficacy of chemotherapy. 1927 65

Estrogen is converted by cytochrome P450 1B1 to 4-hydroxyestradiol (4-OHE(2)), a putative carcinogenic metabolite of estrogen. This catechol estrogen metabolite is oxidized further to produce a reactive quinone via semiquinone. Redox cycling between 4-OHE(2) and its quinoid generates reactive oxygen species (ROS). ROS not only causes oxidative DNA damage but also promotes neoplastic transformation of initiated cells. In the present study, 4-OHE(2) induced anchorage-independent colony formation in human mammary epithelial cells (MCF-10A). MCF-10A cells treated with 4-OHE(2) exhibited increased accumulation of intracellular ROS. The antioxidant N-acetyl-l-cysteine inhibited the neoplastic transformation induced by 4-OHE(2). ROS overproduced by 4-OHE(2) increased the nuclear translocation of nuclear factor-kappaB (NF-kappaB) and its DNA binding through induction of IkappaB kinase alpha (IKKalpha) and IKKbeta activities. The inhibition of the IKK activities with Bay 11-7082 significantly reduced the anchorage-independent growth induced by 4-OHE(2). The 4-OHE(2)-induced activation of extracellular signal-regulated kinase and Akt resulted in enhanced IKK activities and phosphorylation of IkappaBalpha, thereby inducing NF-kappaB activation and anchorage-independent growth of MCF-10A cells. In conclusion, ROS, concomitantly overproduced during redox cycling of 4-OHE(2), activates IKK signaling, which may contribute to neoplastic transformation of MCF-10A cells.
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PMID:4-hydroxyestradiol induces anchorage-independent growth of human mammary epithelial cells via activation of IkappaB kinase: potential role of reactive oxygen species. 1927 83

Tumor malignancy is associated with several features such as proliferation ability and frequency of metastasis. Connective tissue growth factor (CTGF), a secreted protein that binds to integrins, modulates the invasive behavior of certain human cancer cells. However, the effect of CTGF on migration activity in human chondrosarcoma cells is mostly unknown. Here we found that CTGF increased the migration and expression of matrix metalloproteinase (MMP)-13 in human chondrosarcoma cells (JJ012 cells). RGD peptide, alphavbeta3 monoclonal antibody (mAb) and MAPK kinase (MEK) inhibitors (PD98059 and U0126) but not RAD peptide inhibited the CTGF-induced increase of the migration and MMP-13 up-regulation of chondrosarcoma cells. CTGF stimulation increased the phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK). In addition, treatment of JJ012 cells with NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) inhibited CTGF-induced cell migration and MMP-13 up-regulation. Stimulation of JJ012 cells with CTGF also induced IkappaB kinase alpha/beta (IKK alpha/beta) phosphorylation, IkappaBalpha phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. The CTGF-mediated increases in kappaB-luciferase activities were inhibited by RGD, PD98059, U0126 or FAK, and ERK2 mutant. Taken together, our results indicated that CTGF enhances the migration of chondrosarcoma cells by increasing MMP-13 expression through the alphavbeta3 integrin, FAK, ERK, and NF-kappaB signal transduction pathway.
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PMID:CTGF enhances migration and MMP-13 up-regulation via alphavbeta3 integrin, FAK, ERK, and NF-kappaB-dependent pathway in human chondrosarcoma cells. 1930 Dec 59

Several sesquiterpene lactones that have been isolated from medicinal plants are known to have many pharmacological activities. In this study, we investigated the anti-inflammatory effects of zedoarondiol, a sesquiterpene lactone isolated from the rhizoma of Curcuma heyneana, in lipopolysaccharide (LPS)-stimulated macrophage cells. Zedoarondiol dose-dependently inhibited LPS-stimulated nitric oxide (NO), prostaglandin E(2) (PGE(2)), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta) productions in RAW 264.7 macrophage and in mouse peritoneal macrophage cells. Consistent with these findings, in RAW 264.7 cells, zedoarondiol suppressed the LPS-stimulated protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and the mRNA expressions of iNOS, COX-2, TNF-alpha, IL-6, and IL-1beta in a concentration-dependent manner. Moreover, molecular data revealed that zedoarondiol inhibited LPS-stimulated DNA binding activity and the transcription activity of nuclear factor-kappa B (NF-kappaB), and this effect was accompanied by decreases in the degradation and phosphorylation of inhibitory kappaB (IkappaB)-alpha, and in the subsequent blocking of NF-kappaB translocations to the nucleus. Furthermore, zedoarondiol attenuated the phosphorylations of IkappaB kinase (IKK), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38), and c-Jun N-terminal kinase (JNK) in LPS-stimulated RAW 264.7 cells. Taken together, the findings of the present study indicate that zedoarondiol inhibits iNOS, COX-2, and pro-inflammatory cytokine expressions by suppressing the phosphorylations of IKK and MAPKs, and by subsequently inactivating the NF-kappaB pathway. These relations reveal, in part, the mechanism underlying the anti-inflammatory properties of zedoarondiol.
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PMID:Zedoarondiol isolated from the rhizoma of Curcuma heyneana is involved in the inhibition of iNOS, COX-2 and pro-inflammatory cytokines via the downregulation of NF-kappaB pathway in LPS-stimulated murine macrophages. 1939 40

Comparative analysis of hepatocellular carcinoma (HCC) in rat strains that are either susceptible or resistant to the induction of HCC has allowed the mapping of genes responsible for inherited predisposition to HCC. These studies show that the activity of several low penetrance genes and a predominant susceptibility gene regulate the development of hepatocarcinogenesis in rodents. These studies shed light on the epidemiology of human HCC. The identified genes regulate resistance to hepatocarcinogenesis by affecting the capacity of the initiated cells to grow autonomously and to progress to HCC. Analysis of the molecular alterations showed highest iNos cross-talk with IKK/NF-kB and RAS/ERK pathways in most aggressive liver lesions represented by HCC in the susceptible F344 rats. Unrestrained extracellular signal-regulated kinase (Erk) activity linked to proteasomal degradation of dual-specificity phosphatase 1 (Dusp1), a specific ERK inhibitor, by the CKS1-SKP2 ubiquitin ligase complex was highest in more aggressive HCC of genetically susceptible rats. Furthermore, deregulation of G1 and S phases of the cell cycle occurs in HCC of susceptible F344 rats, leading to pRb hyperphosphorylation and elevated DNA synthesis, whereas a block to G1-S transition is present in the HCC of resistant BN rats. Importantly, similar alterations in the signaling pathways that regulate cell cycle progression were found in human HCC with poorer prognosis (as defend by patients' survival length), whereas human HCC with better prognosis had molecular characteristics similar to the lesions in the HCC of resistant rat strains. This review discusses the role of molecular alterations involved in the acquisition of resistance or susceptibility to HCC and the importance of genetically susceptible and resistant rat models for the identification of prognostic markers, and chemopreventive or therapeutic targets for the biological network therapy of human disease.
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PMID:Genetic and epigenetic control of molecular alterations in hepatocellular carcinoma. 1942 55

Tumor malignancy is associated with several features such as proliferation ability and frequency of metastasis. Osteopontin (OPN), which abundantly expressed in bone matrix, is involved in cell adhesion, migration, invasion and proliferation via interaction with its receptor, that is, alphavbeta3 integrin. However, the effect of OPN on migration activity in human chondrosarcoma cells is mostly unknown. Here we found that OPN increased the migration and expression of matrix metalloproteinase (MMP)-9 in human chondrosarcoma cells (JJ012 cells). RGD peptide, alphavbeta3 monoclonal antibody and MAPK kinase (MEK) inhibitors (PD98059 and U0126) but not RAD peptide inhibited the OPN-induced increase of the migration and MMP-9 up-regulation of chondrosarcoma cells. OPN stimulation increased the phosphorylation of focal adhesion kinase (FAK), MEK and extracellular signal-regulated kinase (ERK). In addition, treatment of JJ012 cells with NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) inhibited OPN-induced cell migration and MMP-9 up-regulation. Stimulation of JJ012 cells with OPN also induced IkappaB kinase alpha/beta (IKK alpha/beta) phosphorylation, IkappaBalpha phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. The OPN-mediated increases in MMP-9 and kappaB-luciferase activities were inhibited by RGD peptide, PD98059 or FAK and ERK2 mutant. Taken together, our results indicated that OPN enhances the migration of chondrosarcoma cells by increasing MMP-9 expression through the alphavbeta3 integrin, FAK, MEK, ERK and NF-kappaB signal transduction pathway.
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PMID:Osteopontin increases migration and MMP-9 up-regulation via alphavbeta3 integrin, FAK, ERK, and NF-kappaB-dependent pathway in human chondrosarcoma cells. 1947 68

Adiponectin is an adipokine with potent anti-inflammatory properties. We previously reported that a globular adiponectin (gAd) suppresses Aggregatibacter actinomycetemcomitans lipopolysaccharide-induced nuclear factor-kappaB activity, suggesting an anti-inflammatory effect of gAd. In this study, we investigated whether gAd is able to modulate the effect of A. actinomycetemcomitans lipopolysaccharide on cytokine induction in a murine macrophage cell line (RAW 264). The phosphorylation of p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and IkappaB kinase alpha/beta and the degradation of IkappaB, which were induced by A. actinomycetemcomitans lipopolysaccharide intoxication, were clearly reduced in gAd-pretreated RAW 264 cells compared with the untreated cells. Expression levels of tumor necrosis factor (TNF)-alpha and interleukin-10 (IL-10) mRNA were assessed by real-time PCR. Cell-free supernatants were collected after 12 h of stimulation and analyzed by enzyme-linked immunosorbent assay for TNF-alpha and IL-10. Pretreatment with gAd significantly inhibited the A. actinomycetemcomitans lipopolysaccharide-induced TNF-alpha mRNA expression and protein secretion. In contrast, pretreatment with gAd significantly enhanced the A. actinomycetemcomitans lipopolysaccharide-induced IL-10 mRNA expression and protein secretion. These data suggest a mechanism for the anti-inflammatory activity of gAd in local inflammatory lesions, such as periodontitis.
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PMID:Anti-inflammatory activity of a globular adiponectin function on RAW 264 cells stimulated by lipopolysaccharide from Aggregatibacter actinomycetemcomitans. 1955 15

In a phenotypic screen of the wild-derived mouse strain MOLF/Ei, we describe an earlier and more potent toll-like receptor (TLR)-mediated induction of IL-6 transcription compared with the classical inbred strain C57BL/6J. The phenotype correlated with increased activity of the IkappaB kinase axis as well as p38, but not extracellular signal-regulated kinase or c-Jun N-terminal kinase, mitogen-activated protein kinase (MAPK) phosphorylation. The trait was mapped to the Why1 locus, which contains Irak2, a gene previously implicated as sustaining the late phase of TLR responses. In the MOLF/Ei TLR signaling network, IRAK-2 promotes early nuclear factor kappaB (NF-kappaB) activity and is essential for the activation of p38 MAPK. We identify a deletion in the MOLF/Ei promoter of the inhibitory Irak2c gene, leading to an increased ratio of pro- to antiinflammatory IRAK-2 isoforms. These findings demonstrate that IRAK-2 is an essential component of the early TLR response in MOLF/Ei mice and show a distinct pathway of p38 and NF-kappaB activation in this model organism. In addition, they demonstrate that studies in evolutionarily divergent model organisms are essential to complete dissection of signal transduction pathways.
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PMID:A mutation in Irak2c identifies IRAK-2 as a central component of the TLR regulatory network of wild-derived mice. 1956 52

There is growing evidence that increased expression of cyclooxygenase-2 (COX-2) in the lungs of patients is a key event in the pathogenesis of lung diseases. In this study, we investigated the involvement of the extracellular signal-regulated kinase (ERK), IkappaB kinase alpha/beta (IKKalpha/beta), and nuclear factor-kappaB (NF-kappaB) signaling pathways in thrombin-induced COX-2 expression in human lung fibroblasts (WI-38). Treatment of WI-38 cells with thrombin caused increased COX-2 expression in a concentration- and time-dependent manner. Treatment of WI-38 cells with PD 98059 (2-[2-amino-3-methoxyphenyl]-4H-1-benzopyran-4-one, a MEK inhibitor) inhibited thrombin-induced COX-2 expression and COX-2-luciferase activity. Stimulation of cells with thrombin caused an increase in ERK phosphorylation in a time-dependent manner. In addition, treatment of WI-38 cells with Bay 117082, an IkappaB phosphorylation inhibitor, and pyrrolidine dithiocarbamate (PDTC), an NF-kappaB inhibitor, inhibited thrombin-induced COX-2 expression. The thrombin-induced increase in COX-2-luciferase activity was also blocked by the dominant negative IkappaBalpha mutant (IkappaBalphaM). Treatment of WI-38 cells with thrombin induced IKKalpha/beta and IkappaBalpha phosphorylation, IkappaBalpha degradation, and kappaB-luciferase activity. The thrombin-mediated increases in IKKalpha/beta phosphorylation and kappaB-luciferase activity were inhibited by PD 98059. Taken together, these results suggest that the ERK-dependent IKKalpha/beta/NF-kappaB signaling pathway plays an important role in thrombin-induced COX-2 expression in human lung fibroblasts.
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PMID:Thrombin induces cyclooxygenase-2 expression via the ERK and NF-kappaB pathways in human lung fibroblasts. 1961 39


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